JPH06128257A - Pyridodiazepine compound - Google Patents

Abstract

PURPOSE:To provide a compound having an excellent antagonistic action against cholecystokinin and gastrin and having a cellular adhesion-inhibiting action and useful as a medicine. CONSTITUTION:A compound of (Ar is halogenated phenyl, etc.; ring A is pyridine ring; R<1>, R<2> are H, halogen, alkyl, etc.; R<3> is ureide, etc.; x is O, S; Y is H, alkyl, etc.; or X and Y are bound to each other to form a triazole ring or imidazole ring), for example, N-(6-(4-chlorophenyl)-9-isopropyl-1-methyl-4H- pyrido[3,2-f]-[1,2,4]triazolo[4,3-a-][1,4]diazepin-4-yl)-N'-(3-methylp henyl)urea. The compound of formula I is obtained by reacting a compound of formula II with an isocyanate compound or isothiocyanate compound of formula: R<24>NCZ (R<24> is H, 1-20C alkyl, aryl, etc.; Z is O or S) in a solvent such as THF at -20 deg.C to the boiling point of the solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyridodiazepine compound or a pharmaceutically acceptable salt thereof which has an excellent antagonistic activity against cholecystokinin and gastrin and an excellent inhibitory effect on cell adhesion.

[0002]

Cholecystokinin (hereinafter, also referred to as CCK) is a neuropeptide consisting of 33 amino acids, and CCK-8 consisting of 8 amino acids on the C-terminal side is also active. Gastrin consists of 34 amino acids, and is active even with pentagastrin consisting of 5 amino acids on the C-terminal side, and the amino acid sequence of pentagastrin is the same as the N-terminal of CCK. Both and their receptors are present in gastrointestinal tissues and central nervous system, and are considered to be involved in the control of pancreatic enzyme secretion and gastric acid secretion, and emotions such as anxiety. Compounds having antagonistic effects on CCK and gastrin are promising as prophylactic or therapeutic agents for diseases such as pancreatic disorders and gastrointestinal ulcers, and also as anxiolytic agents, and many antagonistic substances have been studied to date. Is coming. Benzotrypt [Proceeding of National Academy
Of Science of USA (Proc. Na
tl.Acad.Sci. USA) 78, 6304 (19)
81)], but as a gastrin antagonist, proglumide [Journal of Medicinal Chemistry]
(J.Med.Chem.) 27, 1597 (1984)
Year)] is known. However, these actions are relatively weak, have higher activity, and a compound with excellent safety is desired. Also, for peptide antagonists, the duration of action is short and unstable,
Also, it is not always satisfactory in terms of poor absorbency. Furthermore, in recent years, it has become clear that various cell adhesion molecules are deeply involved in the onset and progression of some inflammatory diseases and allergic diseases, and it has a cell adhesion inhibitory action. It is expected that the compounds can be excellent anti-inflammatory or anti-allergic agents. For example, Proceeding of
National Academy of Sciences of USA (Proc. Natl. Acad. Sci. USA) 8th
8 (1991) 355-359, N- (fluorenyl-9-methoxycarbonyl) amino acids inhibit leukocyte adhesion and thereby suppress the reaction in various animal inflammation models. Federation for Clinical Research Annual Meeting (American Federation for Clinical
In the abstract of Research Annual Meeting, May 6, 1991, it is described that leukocyte adhesion to vascular endothelial cells is inhibited by the inhibition of the expression of adhesion molecules (CD18 etc.) on leukocytes by syngeneic compounds. There is. On the other hand, International Application Publication WO 89/05812 and JP-A-3
JP-A-223290 discloses a thienodiazepine compound having a CCK antagonistic action or a gastrin antagonistic action. Japanese Patent Publication No. 47-9598 discloses a pyridodiazepine compound having an antispasmodic effect. As mentioned above, CCK has been reported to date.
Antagonists and gastrin antagonists are not satisfactory in their effects, and development of compounds having more excellent action is desired. Further, development of excellent anti-inflammatory and anti-allergic agents having an inhibitory effect on leukocyte adhesion to vascular endothelial cells has been desired.

[0003]

Means for Solving the Problems As a result of earnest search for the purpose of developing better CCK antagonists, gastrin antagonists and / or cell adhesion inhibitors, the present inventors have found that
It was found that certain pyridodiazepine compounds have excellent CCK antagonism, gastrin antagonism or an effect of inhibiting leukocyte adhesion to vascular endothelial cells, and completed the present invention.

That is, the present invention has the general formula:

[Chemical 7] [In the formula, Ar represents an aryl which may have a substituent or a heteroaryl which may have a substituent. Ring A represents the following pyridine ring.

[Chemical 8] R ¹ and R ² are the same or different and each have hydrogen, halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, aryl which may have a substituent or a substituent. Optionally represents heteroaryl. Or R
¹ and R ² may be bonded to each other to have a substituent 6
A member ring can be formed. R ³ has the formula: — (CH ₂ ) aN (R ⁴ ) CZN (R ⁵ ) (R ⁶ ) (1) (In the formula, a represents 0 or an integer of 1 to ^6. Z is an oxygen atom or a sulfur atom. R ⁴ is hydrogen and has 1 to 20 carbon atoms.
Represents an aralkyl which may have one alkyl or a substituent. R ⁵ and R ⁶ are the same or different and each represents hydrogen, an alkyl having 1 to 20 carbon atoms, a cycloalkyl which may have a substituent, a cycloalkylalkyl which may have a substituent, and a substituent. The aryl which may have, the aralkyl which may have a substituent, the heteroaryl which may have a substituent, or the heteroarylalkyl which may have a substituent are shown. Group represented by the formula:-(CH ₂ ) aN (R ⁴ ) COR ⁷ (2) (In the formula, a represents 0 or an integer of 1 to 6. R ⁴ is hydrogen and has 1 to 20 carbon atoms. R ⁷ represents an alkyl or aralkyl which may have a substituent, R ⁷ is alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, and 2 carbons.
To 20 alkynyl, aryl optionally having substituent (s), heteroaryl optionally having substituent (s), aralkyl optionally having substituent (s) or hetero optionally having substituent (s) Indicates an arylalkyl. ) By a group represented or _{formula,: - (CH 2) aN} (R 4) SO 2 R 9 (3) - (CH 2) aN (R 4) COOR 10 (4) - (CH 2) aOCON (R ^{11) (R 12) (5} ) - (CH 2) aCON (R 13) (R 14) (6) - (CH 2) aOCOR 15 (7) - (CH 2) aOSO 2 R 16 (8) - ( CH ₂ ) aCOR ¹⁷ (9), and — (CH ₂ ) aS (O) nR ¹⁸ (10) (In the formula, a represents 0 or an integer of 1 to 6. R ⁴ is hydrogen and has 1 to 20 carbon atoms. Aralkyl which may have one alkyl or a substituent, R ⁹ and R ^{10 each} have 1 to ¹⁰ carbon atoms.
20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, substituent An aryl, which may have
The heteroaryl which may have a substituent, the aralkyl which may have a substituent, or the heteroarylalkyl which may have a substituent are shown. R ¹¹ , R ¹² or R ¹³ , R ¹⁴ are the same or different and each have hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, and a substituent. And aryl which may be substituted, heteroaryl which may have a substituent, aralkyl which may have a substituent or heteroarylalkyl which may have a substituent. R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are each 1 to 20 carbon atoms.
Alkyl, aryl optionally having substituent (s), heteroaryl optionally having substituent (s), aralkyl optionally having substituent (s) or heteroarylalkyl optionally having substituent (s) Indicates. n is 0, 1 or 2
Indicates. ) Represents a group selected from. X represents an oxygen atom or a sulfur atom. Y is hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, aralkyl which may have a substituent,
A heteroarylalkyl which may have a substituent, or a formula: — (CH ₂ ) bCOOR ¹⁹ (wherein R ¹⁹ is hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons or Represents an aralkyl which may have a substituent, and b represents an integer of 1 to 6). Or, X and Y are bonded to each other and = NN-C
(R ²⁰⁾ - or = N-CH = C (R 20) - ( wherein,
R ²⁰ is hydrogen, halogen, alkyl having 1 to 20 carbons,
Alkenyl having 2 to 20 carbon atoms, alkynyl having 2 to 20 carbon atoms, cycloalkyl which may have a substituent,
A cycloalkylalkyl which may have a substituent, an aryl which may have a substituent, a heteroaryl which may have a substituent, an aralkyl which may have a substituent, and a substituent A heteroarylalkyl which may have or a formula: — (CH ₂ ) bCOOR ²¹ (wherein R is
²¹ is hydrogen, alkyl having 1 to 20 carbons, 2 to 2 carbons
It represents aralkyl which may have 0 alkenyl or a substituent. b shows the integer of 1-6. ) Shows the group represented by. ) Shows the group represented by. ] The pyridodiazepine compound represented by these, or its pharmaceutically acceptable salt.

Further, the present invention has the general formula

[Chemical 9]

[Chemical 10]

[Chemical 11]

[Chemical 12] (In the formula, each symbol has the same meaning as defined above.) A pyridodiazepine compound or a pharmaceutically acceptable salt thereof.

In the above general formula (I), aryl means
Halogen, alkyl having 1 to 6 carbons, on the aromatic ring,
1 to 3 selected from alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro, amino, cyano and hydroxyl group
And phenyl which may have one substituent, 1-naphthyl, 2-naphthyl and the like. Heteroaryl is a hetero atom constituting the ring is nitrogen, oxygen, sulfur, etc., halogen, alkyl having 1 to 6 carbon atoms,
1 to 3 selected from alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro, amino, cyano and hydroxyl group
May have one substituent, for example, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (2-quinolyl, 3-quinolyl, etc.), indolyl (2-indolyl, 3-indolyl). Etc.), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), benzofuryl (2-benzofuryl,
3-benzofuryl etc.) 1H-benzimidazole-
2-yl, 2-benzothiazolyl and the like can be mentioned. Halogen means chlorine, fluorine, bromine and iodine. The alkyl having 1 to 20 carbon atoms may be linear or branched, and is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, tertiary pentyl, hexyl, octyl. Two
-Ethylhexyl, 2,2-diethyloctyl, 1,
1,3,3-tetramethylbutyl, nonyl, decyl, dodecyl, tetradecyl, octadecyl, eicosyl and the like can be mentioned. The alkyl preferably has 1 to 6 carbon atoms. Aralkyl which may have a substituent has 1 to 6 carbon atoms in the alkyl part, preferably 1 to 4 carbon atoms, halogen on the aromatic ring, alkyl having 1 to 6 carbon atoms, It may have 1 to 3 substituents selected from alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro, amino, cyano and hydroxyl group, benzyl, 1-
Phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,
6-phenylhexyl, 1-naphthylmethyl, 2-naphthylmethyl, diphenylmethyl, 4-phenyl-3-methylbutyl and the like can be mentioned.

Alkenyl having 2 to 20 carbon atoms means vinyl, propenyl, 2-methyl-1-propenyl, 3-methyl-1-butenyl, 2,3-dimethyl-1-butenyl, 3,4. 5-trimethyl-1-butenyl, 3-butenyl, 3-hexenyl, 5-dodecenyl, 6-ethyl-
Examples thereof include 3-decenyl, 11,11-dimethyl-7-tetradecenyl, 14-octadecenyl, 8-eicosenyl and the like. Preferred alkenyl has 2 to 8 carbon atoms.
It is an individual. Alkynyl having 2 to 20 carbon atoms means 1-propynyl, 3-methyl-1-butynyl, 1,4-dimethyl-1-hexynyl, ethynyl, propargyl, 3-hexynyl, 3,4-diethyl-1-octynyl. , 5-dodecynyl, 6-ethyl-3-decynyl, 11,11-dimethyl-7-tetradecynyl, 14-octadecynyl,
8-eicosinyl and the like can be mentioned. The alkynyl preferably has 2 to 8 carbon atoms. The cycloalkyl which may have a substituent has 3 to 10 carbon atoms,
For example, cyclopropyl, 2,3-dimethylcyclopropyl, cyclobutyl, 3-methylcyclobutyl, cyclopentyl, 3,4-dimethylcyclopentyl, cyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclooctyl, norbornyl, adamantyl, bicyclo [3 .3.0] octane-1-yl, bicyclo [3.3.1] nonan-9-yl and the like.

The cycloalkyl which may have a substituent means that the cycloalkyl part has 3 to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, and examples thereof include cycloalkyl. Propylmethyl, 2,3-dimethylcyclopropyl, cyclobutylmethyl, 3-methylcyclobutylmethyl, cyclopentylmethyl, 3,4-dimethylcyclopentylmethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, norbornylmethyl, 1-adamantylmethyl, bicyclo [3.3.0] octane-1
-Ylmethyl, bicyclo [3.3.1] nonan-9-ylmethyl and the like. The heteroarylalkyl which may have a substituent is halogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro, amino, cyano and hydroxyl group on the ring. It may have 1 to 3 substituents selected from, and the alkyl part has 1 to 4 carbon atoms, preferably 1 to
The number of hetero atoms constituting two rings is nitrogen, oxygen, sulfur or the like. For example, pyridyl (2
-Pyridyl, 3-pyridyl, 4-pyridyl) methyl, quinolyl (2-quinolyl, 3-quinolyl, etc.) methyl, indolyl (2-indolyl, 3-indolyl, etc.) methyl, thienyl (2-thienyl, 3-thienyl) methyl ,
Furyl (2-furyl, 3-furyl) methyl, benzofuryl (2-benzofuryl, 3-benzofuryl, etc.) methyl, 1H-benzimidazol-2-ylmethyl, 2-
Examples thereof include benzothiazolylmethyl, 2- (2-thienyl) ethyl, 2- (2-furyl) ethyl and the like. R ¹
And a 6-membered ring which may have a substituent formed by combining R ² with each other represents benzene, and the substituent includes halogen, alkyl having 1 to 6 carbons, and 1 to 6 carbons. Individual alkoxy, trifluoromethyl, nitro, cyano, hydroxyl groups and the like. The substituent and halogen in R ¹ and R ² represent chlorine, fluorine, bromine and iodine,
Examples of the alkyl having 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, tertiary pentyl, hexyl and the like. What is alkoxy?
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, isopentyloxy, tertiary pentyloxy, hexyloxy and the like can be mentioned.

Preferred compounds of general formula (I) are:
N- (6- (4-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine-
4-yl) -N '-(3-methylphenyl) urea, N
-(6- (4-chlorophenyl) -9-isopropyl-
1-propyl-4H-pyrido [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine-
4-yl) -N '-(3-methylphenyl) urea, N
-(6- (2-chlorophenyl) -9-isopropyl-
1-methyl-4H-pyrido [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine-
4-yl) -N '-(2-methoxyphenyl) urea,
N- (6- (2-chlorophenyl) -1,9-dimethyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-4 -Ill)-
N '-(4-methoxyphenyl) urea, N- (1-methyl-5-phenyl-2-oxo-1,3-dihydro-
2H-pyrido [2,3-e] [1,4] diazepine-3
-Yl) -N '-(3-methylphenyl) urea, N-
(5- (2-chlorophenyl) -1-methyl-8-isopropyl-2-oxo-1,3-dihydro-2H-pyrido [2,3-e] [1,4] diazepin-3-yl)-
2-indolecarboxamide, N-phenyl- (6-
(4-chlorophenyl) -1-methyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepin-4-yl) acetamide,
N- (3-methylphenyl)-(6- (4-chlorophenyl) -1,9-dimethyl-4H-pyrido [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-4-yl) acetamide, N- (3-
Chlorophenyl)-(6- (4-chlorophenyl) -9
-Isopropyl-1-methyl-4H-pyrido [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-4-yl) acetamide, N- (2-
Methoxyphenyl)-(6- (4-chlorophenyl)-
1-methyl-9-phenyl-4H-pyrido [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-4-yl) acetamide, N- (3-
Methoxyphenyl)-(6- (4-chlorophenyl)-
1-methyl-4H-pyrido [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine-
4-yl) acetamide, N- (6- (4-chlorophenyl) -1,9-dimethyl-4H-pyrido [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-4-yl) -p-toluenesulfonamide, N- (6- (2-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f]
[1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl) -p-toluenesulfonamide,
(5- (4-chlorophenyl) -8-isopropyl-1
-Methyl-2-oxo-1,3-dihydro-2H-pyrido [2,3-e] [1,4] diazepin-3-yl)-
N- (3-methylphenyl) carbamate, (6- (2
-Chlorophenyl) -1,9-dimethyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepin-4-yl) -N- (3-methylphenyl) carbamate, and the like, or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts with inorganic acids or organic acids, and salts with inorganic bases, organic bases or amino acids, and for the purposes of the present invention, these salts. Is preferably non-toxic.
In addition, since the compounds of the general formulas (I), (II), (III) and (IV) have at least one chiral carbon atom, racemic, optically active or diastereomeric compounds based on them Etc. are all included in the present invention.

Method 1: In the general formula (I), the compound in which R ³ is a group represented by the formula (1) is

[Chemical 13] (Wherein each symbol has the same meaning as defined above) and the general formula R ²⁴ NCZ (VI) (wherein R ²⁴ represents R ⁵ or R ⁶ , and R ⁵ , R ⁶ and Z Has the same meaning as defined above.) And an isocyanate or isothiocyanate represented by the formula (1) can be added. The addition reaction between the compound of general formula (V) and the compound of general formula (VI) is carried out in a suitable solvent that does not inhibit this reaction. Examples of the solvent include tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride,
Organic solvents such as ethyl acetate, benzene, toluene, xylene, dimethylformamide and dimethylacetamide are used. The temperature of this reaction varies depending on the reagent and solvent to be used, but in general, -20 ° C to the boiling point of the solvent is preferable.

Method 2: In the general formula (I), a compound in which R ³ is a group represented by the general formula (2) is a compound represented by the general formula (V).
And a compound of the general formula R ⁷ COW (VII) [wherein R ⁷ has the same meaning as defined above, W is a leaving group (hydroxyl group, halogen, ester group (pentachlorophenoxy,
p-nitrophenoxy etc.) or a thioester group (phenylthio, 2,6-dimethylpyridine-4-thio etc.). ] It can manufacture by condensing with the compound represented by these. The condensation reaction between the compound of general formula (V) and the compound of general formula (VII) is carried out in a suitable solvent. As the solvent, tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride,
Using an organic solvent such as ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, etc., if necessary in the presence of a base or a dehydration condensing agent, −2
It is carried out at a temperature from 0 ° C. to the boiling point of the solvent. Bases used as necessary include alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate). Etc.), alkali metal hydrides (such as sodium hydride), or organic bases (triethylamine, pyridine,
Picoline, N-methylmorpholine and the like).
If necessary, a phase transfer catalyst such as tetrabutylammonium bromide or benzyltriethylammonium iodide may be used, and the alkali metal hydroxide may be used in the two-phase system of the above organic solvent and water. As the dehydration condensing agent, those used for amide synthesis are preferable,
For example, dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylaminomethyl) carbodiimide hydrochloride, diphenylphosphoryl azide, N
-Methyl-2-chloropyridinium iodide and the like.

Method 3: The compound of the general formula (V) is added to a base (triethylamine, pyridine, if necessary) in an inert solvent such as dichloromethane, chloroform, benzene, toluene, carbon tetrachloride, tetrahydrofuran or dioxane.
In the presence of N-methylmorpholine, etc.), it is represented by the general formula: Q-SO ₂ R ⁹ (VIII) (in the formula, Q represents halogen such as chlorine, and other symbols have the same meanings as described above). By reacting with a sulfonic acid halide, the general formula:

[Chemical 14] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained.

Method 4: The compound of the general formula (V) is treated with an inert solvent such as chloroform, dichloromethane, benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane and the like, represented by the general formula Q-COOR ¹⁰ (IX) Has the same meaning as defined above), and is reacted with a halide represented by the general formula:

[Chemical 15] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained.

Method 5: A compound of the general formula: Q-CON (R ¹¹ ) (R ¹² ) (R ¹² ) (R ¹² ) (N) in an inert solvent such as dichloromethane, chloroform, benzene, toluene, dimethylformamide or carbon tetrachloride. X) (wherein each symbol has the same meaning as defined above) or is reacted with a halide represented by the general formula: OCN-R ²⁸ (XI) (wherein R ²⁸ is R ¹¹ or R ¹² By the reaction with an isocyanate represented by the general formula

[Chemical 16] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained.

Method 6: A compound represented by the general formula (IV) is reacted with a compound represented by the general formula HN (R ¹³ ) (R ¹⁴ ) (XII) (wherein each symbol has the same meaning as defined above). By the general formula

[Chemical 17] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained. The reaction is carried out in a suitable solvent (tetrahydrofuran, diethyl ether, diisopropyl ether,
An organic solvent such as dioxane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide) in the presence of a base or a dehydration condensing agent, if necessary.
A temperature of 20 ° C. to the boiling point of the solvent is used. As a base used if necessary, triethylamine, pyridine,
Examples thereof include N-methylmorpholine. As the dehydration condensing agent, those usually used for peptide synthesis are preferable, and examples thereof include dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylaminomethyl) carbodiimide hydrochloride, diphenylphosphoryl azide, N-methyl-2. -Chloropyridinium iodide, molecular sieve and the like.

Method 7: The compound of the general formula (III) is treated with a compound of the general formula Q-COR ¹⁵ (XIII) in the inert solvent such as dichloromethane, chloroform, benzene, toluene, dimethylformamide and carbon tetrachloride. Has the same meaning as defined above.) Or an acid represented by the general formula (R ¹⁵ CO) ₂ O (XIV) (wherein the symbols have the same meanings as defined above). By reacting with an anhydride, the general formula

[Chemical 18] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained.

Method 8: By reacting a compound represented by the general formula (III) with a compound represented by the general formula Q-SO ₂ R ¹⁶ (XV) (wherein each symbol has the same meaning as defined above), General formula

[Chemical 19] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained.

Method 9: General formula

[Chemical 20] (Wherein each symbol has the same meaning as defined above), the compound represented by the formula (I) is used in the presence of a base such as sodium hydride, potassium tertiary butoxide, lithium diisopropylamide or butyl lithium. By introducing an alkoxycarbonyl group at the 3-position, and then reacting with a halide of the general formula Q- (CH ₂ ) aCOR ¹⁷ (XVII) (wherein each symbol has the same meaning as described above), General formula obtained

[Chemical 21] (In the formula, R ²⁹ represents alkyl such as methyl and ethyl,
Each other symbol has the same meaning as above. In the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, barium hydroxide, etc., water or water and a suitable solvent (methanol, ethanol, tetrahydrofuran, dioxane) can be used. Etc.) in a mixed solvent with a temperature of from 0 ° C. to the boiling point of the solvent used, and further using an acid (hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.) By carrying out a decarboxylation reaction,
General formula

[Chemical formula 22] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained.

Method 10: A compound of the general formula (III) is treated with phosphorus oxychloride, phosphorus tribromide, chlorine, bromine, in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane or dimethylformamide.
It is halogenated by reacting it with a halogenating agent such as N-bromosuccinimide, and this is halogenated in a suitable solvent (methanol, ethanol, dimethylacetamide, dimethylformamide, etc.) and represented by the general formula R ¹⁸ SH or R ¹⁸ SNa (XIX) ( In the formula, R ¹⁸ has the same meaning as described above.) By reacting with a thiol or thiolate represented by the general formula

[Chemical formula 23] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained. When this compound is oxidized with an oxidant (hydrogen peroxide, potassium permanganate, sodium hypochlorite, ozone, ruthenium oxide, etc.) in a mixed solvent of ethanol, methanol, acetic acid or acetic acid and water, the general formula

[Chemical formula 24] (In the formula, n'represents 1 or 2, and other symbols have the same meanings as described above.).

A general formula in which a is 0 in the general formula (II)

[Chemical 25] (Wherein each symbol has the same meaning as defined above), the compound of the general formula (XVI) is a base (sodium hydride, potassium tertiary butoxide, lithium diisopropylamide,
Butyllithium, etc.) to react with a dialkyl carbonate (diethyl carbonate, etc.) to introduce an alkoxycarbonyl group (ethoxycarbonyl, etc.) at the 6-position, and then O-
General formula by reacting with (2,4-dinitrophenyl) hydroxylamine

[Chemical formula 26] (Wherein R ²⁵ represents alkyl such as ethyl, and other symbols have the same meanings as described above.),
The compound of the general formula (XX) is converted into a base (sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.)
In the presence of water, or in a mixed solvent of water and an organic solvent (preferably methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane, etc.), at a temperature from about 0 ° C. to the boiling point of the solvent used Then, the obtained reaction solution is acidified with an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, and decarboxylated.

In the general formula (V), the compound in which a is 1 to 6 is prepared by introducing an alkoxycarbonyl in the same manner as described above,

[Chemical 27] (In the formula, a ′ represents an integer of 1 to 6, and Q represents halogen.)
By reacting the compound represented by

[Chemical 28] (In the formula, Phth represents phthaloyl and other symbols have the same meanings as described above.), And a compound represented by the general formula (XXII) was prepared by using a base (sodium hydroxide, potassium hydroxide, water). In the presence of barium oxide, lithium hydroxide, etc.) or a mixed solvent of water and an organic solvent (methanol, ethanol, diethyl ether, tetrahydrofuran, dioxane, etc. are preferable), from about 0 ° C. to the boiling point of the solvent used. Dehydrocarbonation was carried out by subjecting the resulting reaction solution to hydrolysis with an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or trifluoromethanesulfonic acid at a temperature of Hydride in a suitable solvent (water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane, or a mixture of these) Jin added, by deprotecting at a temperature up to the boiling point of the solvent used 0 ° C., the general formula

[Chemical 29] (In the formula, each symbol has the same meaning as above.).

The compound of the general formula (V) can be obtained by the general formula (II-1) or the general formula (II-).
Suitable as the compound of 2) is an alkyl halide represented by the general formula R ⁴ Q (XXIII) (wherein Q represents halogen and R ⁴ has the same meaning as above but represents a group other than hydrogen). Solvent (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, etc.)
Medium, base (sodium hydride, potassium tertiary butoxide, lithium diisopropylamide, butyl lithium,
-20 ° C in the presence of pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc.)
To the boiling point of the solvent used, or by reacting with an aldehyde in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride.

In the general formula (III), the compound in which a is 0 can be synthesized by the synthetic route shown below.

[Chemical 30] (In the formula, each symbol has the same meaning as described above.) The compound of the general formula (XVI) is converted into chloroform, carbon tetrachloride, dichloroethane,
N-oxide (XXIV) was converted to peroxidic acid such as metachloroperbenzoic acid, hydrogen peroxide and peracetic acid in an inert solvent such as benzene and toluene, and this was subjected to a Poronovsky rearrangement reaction in acetic anhydride to give a general formula ( XXV), and then react with a base such as sodium hydroxide, barium hydroxide, potassium hydroxide in a mixed solution of water and an appropriate organic solvent (methanol, ethanol, isopropyl alcohol, etc.). By hydrolysis with the general formula (I
The compound of II-1) is obtained.

In the compound of the general formula (III), wherein a is 1 to 6, the compound of the general formula (XVI) is introduced with an alkoxycarbonyl group at the 3-position and then the compound of the general formula Q- ( CH ₂ ) aOCOR '(XXVI) (In the formula, R'represents alkyl such as methyl or ethyl,
Other symbols are as defined above. A general formula obtained by reacting a halide represented by

[Chemical 31] (In the formula, each symbol has the same meaning as above.) The compound is synthesized by decarboxylation and hydrolysis in the same manner as above. In the general formula (III), the compound in which a is 1 to 6 is obtained by reacting the compound of the general formula (XVI) with a base (sodium hydride) in an inert solvent such as tetrahydrofuran, dioxane, diethyl ether, benzene, toluene or dimethylformamide. , Potassium tert-butoxide, lithium diisopropylamide, butyllithium, etc.) in the presence of the formula:
Q- (CH ₂₎ aNPhth or formula: Q-(C
It can also be directly obtained by reacting with H ₂ ) aOCOR '(wherein each symbol has the same meaning as defined above). This reaction usually proceeds at 0 ° C. or lower to −50 ° C., and can be synthesized by deprotecting and hydrolyzing each of the obtained compounds.

The compound of general formula (IV) can be synthesized by the synthetic route shown below.

[Chemical 32] (In the formula, each symbol has the same meaning as described above.) The compound of the general formula (XVI) is treated with carbonic acid such as diethyl carbonate in the presence of a base such as sodium hydride, potassium tertiary butoxide, lithium diisopropylamide and butyllithium. An alkoxycarbonyl group such as an ethoxycarbonyl group is introduced at the 3-position of the diazepine ring by reacting with a dialkyl, and then a compound represented by the general formula Q
When a haloester represented by — (CH ₂ ) aCOOR ′ (where R ′, Q and a have the same meanings as defined above) is reacted, a compound of the general formula (XXIX) is obtained. Compound of general formula (XXIX) in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, barium hydroxide, or water and a suitable solvent (methanol, ethanol, tetrahydrofuran, In a mixed solvent with dioxane), the hydrolysis reaction is performed at a temperature from 0 ° C to the boiling point of the solvent used, and then an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or trifluoromethanesulfonic acid is used. The compound of general formula (IV) is obtained by acidifying the mixture with acid to carry out a decarboxylation reaction.

The compounds of the general formulas (I), (II), (III) and (IV) of the present invention thus obtained are obtained by a method known per se such as recrystallization and column chromatography.
It can be separated and purified from the reaction mixture. The compound of the present invention is prepared by a conventional method using an inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid,
Phosphoric acid, nitric acid, etc.), organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, ascorbic acid, etc.), Inorganic base (sodium hydroxide, potassium hydroxide, calcium hydroxide,
Magnesium hydroxide, zinc hydroxide, ammonium hydroxide, etc., organic bases (methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethylaminomethane, quinine, guanidine, cinchonine, etc.) or amino acids (lysine) , Ornithine, arginine, alanine, etc.) to form a salt. Also included are hydrates and other solvates. When the compound of the present invention has a chiral carbon atom, it is usually obtained as a racemate. The racemate can be resolved into optical isomers by a conventional method. Such optical isomers can also be prepared by using optically active starting materials. Individual diastereomers can be purified by fractional crystallization or chromatography.

The general formula

[Chemical 33] (Wherein each symbol has the same meaning as defined above) and by synthesizing the compound according to the method described in JP-A-1-156982, JP-A-1-79185 and the like. , General formula

[Chemical 34] (Wherein each symbol has the same meaning as defined above) and the general formula

[Chemical 35] (In the formula, each symbol has the same meaning as defined above.) A compound represented by the above is obtained. Also, in the general formula (XVI),

[Chemical 36] (Wherein each symbol has the same meaning as defined above), the compound represented by the general formula (XVI
General formula synthesized from the compound of -1)

[Chemical 37] (In the formula, each symbol has the same meaning as described above.)

[Chemical 38] (Wherein R ²⁷ represents alkyl such as methyl and ethyl or aralkyl such as benzyl, and R ²⁰ has the same meaning as described above), and is produced. The reaction is usually carried out in a solvent inert to the reaction (methanol, ethanol, dioxane, dimethylformamide, tetrahydrofuran, benzene, toluene, xylene or a mixed solvent thereof) with an acid catalyst (hydrochloric acid,
In the presence of mineral acids such as sulfuric acid and polyphosphoric acid, lower fatty acids such as formic acid, acetic acid and propionic acid, organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, etc., at room temperature to 150 ° C., preferably in a solvent. It is carried out under reflux.
During the reaction, when the acid catalyst itself is in a liquid state, it can also serve as a solvent.

[0029]

The compounds of the general formula (I) and salts thereof of the present invention have excellent cholecystokinin and gastrin antagonism, and exhibit potent and long lasting pancreatic enzyme and gastric acid secretion inhibitory effects. Therefore, it is useful as a drug that acts on central and peripheral nerves and as a preventive or therapeutic drug for pancreatic disorders and gastrointestinal ulcers. Further, the compound of the present invention can be expected to have an anxiolytic action based on the cholecystokinin antagonistic action, and is also useful as an anxiolytic drug. Next, the pharmacological test method of the compound of the present invention will be shown. Experimental Example 1: Cholecystokinin Receptor Binding Test Homogenize 20% volume of rat cerebral cortex in ice-cooled 0.32 M sucrose solution (Polytron, 15,000 r).
Centrifuge at 1,000 g for 10 minutes).
The supernatant is further centrifuged at 40,000 g for 15 minutes. 10 mM HEPES buffer (pH 7.4, 130 mM NaCl, 5 mM MgC) for the purpose of washing the obtained pellet.
homogenized to include a l ₂₎ (Polytron, 15,00
The operation of 0 rpm for 10 seconds) -centrifugation (40,000 g, 10 minutes) is performed twice. 3 of the finally obtained pellets
Zero volume of assay buffer (130 mM NaCl, 5
mM MgCl ₂ , 0.02% bacitracin, 1 mg /
l Phenylmethanesulfonyl fluoride containing 5 mM
HEPES, pH 6.5) is homogenized (Polytron, 15,000 rpm for 20 seconds) and used as a synaptic membrane preparation. ³ H-CCK _{8 in} 0.9 ml of synaptic membrane sample
50 μl (final concentration 0.5 nM) and 50 μl of test solution or solvent were added, reacted at 22 ° C. for 40 minutes, suction filtered with glass fiber filter paper (Whatman GF / B), and immediately ice-cooled 10 mM HEPES buffer (pH 7.4). ) 3m
Wash 3 times with 1 and measure the radioactivity concentration on the filter paper. 1μ
MCCK ₈ and the amount of non-specific binding amount bound in the presence. Experimental Example 2: Cholecystokinin receptor binding test Rat pancreas was chilled with 20 volumes of ice-cold 10 mM HEPES.
Buffer solution (pH 7.4, 130 mM NaCl, 5 mM
Homogenize (including MgCl ₂ ) (Polytron, 1
5,000 rpm for 60 seconds), 40,000g, 1
Centrifuge for 5 minutes. 10 for the purpose of washing the obtained pellet.
Homogenize in mM HEPES buffer (Polytron,
Centrifuge (40,000 at 15,000 rpm for 10 seconds)
g, 10 minutes). The finally obtained pellet was mixed with 60 volumes of assay buffer (130 mM N
aCl, 5 mM MgCl ₂ , 0.02% bacitracin, 1 mg / l phenylmethanesulfonyl fluoride-containing 10 mM HEPES, pH 7.4), homogenize (Polytron, 15,000 rpm for 20 seconds)
And use it as a synaptic membrane specimen. Synaptic membrane preparation 0.9 ml
50 μl of ³ H-CCK ₈ (final concentration 0.5 nM) and 50 μl of test solution or solvent were added, reacted at 22 ° C. for 60 minutes, suction filtered with glass fiber filter paper (Whatman GF / B), and immediately cooled with ice to 10 mM HEPES buffer. Liquid (p
H7.4) Wash 3 times with 3 ml, and measure the radioactivity concentration on the filter paper. The binding amount in the presence of 1 μM CCK _{8 is} defined as the non-specific binding amount. CCK in Experimental Example 1 and Experimental Example 2
The effect of the test compound in the receptor binding test is determined by the inhibition rate according to the following formula, and evaluated by the concentration at which specific binding is suppressed by 50% (IC ₅₀ ).

Further, the compound of the general formula (I) of the present invention has an action of inhibiting leukocyte adhesion to vascular endothelial cells by suppressing the expression of CD18 on leukocytes, and also inhibits leukocyte infiltration in vivo. Also suppress. Due to this action, the present compound is expected to be useful as a therapeutic or prophylactic agent for various inflammatory diseases, allergic diseases, etc. in which cell adhesion is involved in the onset / progress thereof, and also autoimmune diseases and pancreas transplantation. It can be used to prevent or treat temporal rejection and also to prevent metastasis of tumor cells. The pharmacological test method is shown below. Experimental Example 3: U to cultured human vascular endothelial cells (HUVEC)
937 cell (human histiocytic leukemia cell) adhesion inhibitory action HUVEC was added to fetal bovine serum (20%), bovine brain-derived vascular endothelial cell growth factor (20 μg / ml) and heparin (10%).
It is suspended in a 199 medium containing 0 μg / ml), added to a 96-well tissue culture plate coated with collagen, and cultured at 37 ° C. in the presence of 5% CO ₂ . Interleukin 1 (10 U when the cells reached confluence)
/ Ml), and the cells are further cultured for 24 hours. After washing
U937 cells (3 × 10 ⁵ cells / well) were added together with leukotriene B4 (1 μM) and the test compound, and 3
Incubate for 0 minutes. After removing the non-adherent cells by inverting the plate, Rose Bengal solution (0.25% in phosphate buffered saline) is added and left for 5 minutes. Non-adherent cells were washed and removed twice using 199 medium, 50% ethanol diluted with phosphate buffered saline was added, and the mixture was allowed to stand for 20 minutes to leak the rose bengal dye incorporated into the cells. Let The absorbance at 570 nm was measured using a 96-well plate absorbance meter, and the value obtained by subtracting the absorbance of the HUVEC-only well was used as an index for U937 cell adhesion. Experimental Example 4: Effect on human peripheral blood neutrophil CD18 expression LFA-1 (lymphocyte function associated antigen-1 (lymphocyte function a), which is one of the adhesion molecules expressed on the surface of most leukocyte cells.
The effect of the ssociated antigen-1)) on the expression of the CD18 antigen constituting the β chain is examined. Human peripheral blood neutrophils prepared with dextran were suspended in RPMI1640 medium containing fetal bovine serum (20%) to give leukotriene B.
Add 4 (1 μM) and test compound to 96-well filtration plate (2 × 10 ⁵ cells / well). 37
After culturing at 90 ° C in the presence of 5% CO ₂ for 90 minutes, RPMI
After washing once with 1640 medium, mouse anti-human CD18 monoclonal antibody (4 μg / ml) is added. After leaving it for 1 hour under ice cooling, it was washed once, and peroxidase-labeled anti-mouse immunoglobulin antibody (2.5 μg / ml)
Is added. After leaving it for 1 hour under ice cooling, wash twice,
A substrate for peroxidase, [2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)] is added. After leaving at room temperature for 30 minutes, the absorbance at 405 nm is measured using an absorptiometer for 96-well plate,
It is used as an index of CD18 antigen expression. Experimental Example 5: Effect on oxazolone-induced mouse ear edema After sensitization by applying 50 μl of an oxazolone solution (50 mg / ml in acetone) to the abdomen of a mouse from which hair had been removed, 5 μl each was applied to the front and back of the right ear of the mouse on the 6th day. Apply the oxazolone solution. After 24 hours, the left and right ears are hollowed out using a puncher having a diameter of 6 mm, and the weight thereof is measured by a direct balance. The value obtained by subtracting the weight of the untreated (left ear) from the weight of the treated ear (right ear) is used as an index of edema. The test compound is suspended in a 0.5% methylcellulose solution and orally administered 3 to 6 days after sensitization (0.1 ml / 10 g body weight).

When the compound of the present invention and a pharmaceutically acceptable salt thereof are used as a medicine, usually, a pharmaceutically acceptable additive such as carrier, excipient, diluent, solubilizing agent (lactose, corn starch, Mix talc, kaolin, physiological saline, sterilized water, etc.) to tablets in the form of tablets (including sugar-coated tablets, film-coated tablets), capsules, powders, injections, drops, suppositories, and poultices. It can be safely administered. The dose may vary depending on the sex, age, weight or symptom of the patient, but it is usually about 1 to 50 per day for an adult.
A range of 0 mg is preferred. Further, the general formula (II), (III),
The compound of formula (IV) is useful as a synthetic intermediate for the compound of formula (I).

[0032]

EXAMPLES The present invention will be specifically described below with reference to Examples, but it goes without saying that the present invention is not limited to these. Starting Material Preparation Example 1 2-amino-3- (4-chlorobenzoyl) -5-isopropylpyridine (10.0 g) is dissolved in pyridine (200 ml), glycine ethyl ester hydrochloride (10.0 g) is added, and the mixture is heated under reflux for 15 hours. Glycine ethyl ester (10 g) was added to the reaction solution, and the mixture was refluxed for 15 hours.
After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and ethyl acetate was added to the residue. 1N Hydrochloric acid was added to this solution to wash the organic layer, which was further washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give an orange oil. This residue was subjected to silica gel column chromatography, and the solution eluted with a chloroform-methanol (10: 1) eluent was concentrated to give a slightly yellow 5- (4-chlorophenyl) -1,3-dihydro-8-isopropyl. −
2H-pyrido [2,3-e] -1,4-diazepine-2
-Giving 6.3 g of on. This is recrystallized from methanol to obtain a pale yellow powder crystal having a melting point of 189 to 190 ° C. Raw Material Preparation Example 2 3- (4-chlorobenzoyl) -2-aminopyridine 5.7 g, pyridine 3.9 g and chloroform 50 m
l was added to make a uniform solution, 7.3 g of N-phthaloylaminoacetic acid chloride was added at room temperature, and the reaction solution was heated under reflux for 2 hours. After the reaction, the reaction solution was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an orange residue. Add a small amount of ethanol to this to crystallize,
When collected by filtration, 7.6 g of 2- (N-phthalylalanyl) amino-3- (4-chlorobenzoyl) pyridine having a melting point of 198 to 200 ° C. was mixed with 2- (N-phthalylalanyl) amino-3- (4-chlorobenzoyl) pyridine. 0.42 g and 4 ml of ethanol were added to make a uniform solution, 0.12 g of hydrazine monohydrate was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction, the precipitated crystals were collected by filtration, washed with a small amount of ethanol and then dried to give white crystals of 3- (4-chlorobenzoyl) -2- [N- (2-hydrazinocarbonyl) benzoylalanyl. ] 0.34 g of pyridine was obtained. Melting point 220 ° C (decomposition). 9.0 g of 3- (4-chlorobenzoyl) -2- [N- (2-hydrazinocarbonyl) benzoylalanyl] pyridine and 400 ml of toluene
The solution of was heated to reflux for 15 hours. After the reaction, the reaction solution is concentrated under reduced pressure to remove toluene, chloroform is added, and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized from chloroform to give white powdery crystals of 5- (4-chlorophenyl) -1,3-dihydro-2H-pyrido [2,3-e].
4 g of -1,4-diazepin-2-one was obtained. Melting point 25
4-255 ° C.

Reference Example 1 5- (4-chlorophenyl) -1, obtained in Raw Material Preparation Example 1,
3-dihydro-8-isopropyl-2H-pyrido [2,2
3-e] -1,4-diazepin-2-one (5.5 g) and chloroform (180 ml) were added to a homogeneous solution of phosphorus pentasulfide (5.
Add 84 g and stir at room temperature for 2 hours. After the reaction, the reaction solution is poured into water and extracted with chloroform. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give an orange oil. The residue was subjected to silica gel column chromatography, and chloroform-ethyl acetate (1
The solution obtained by eluting with the mixed solution of 00: 1) is concentrated under reduced pressure to obtain 5.5 g of pale yellow crystals. When recrystallized from ethanol, 5- (4-chlorophenyl) -1,3
-Dihydro-8-isopropyl-2H-pyrido [2,3
-E] -1,4-diazepine-2-thione is obtained as a slightly yellow powdery crystal. Melting point 201 to 202 ° C. 2.0 g of the obtained thione compound is uniformly dissolved in 20 ml of chloroform and 20 ml of methanol, and 0.6 ml of hydrazine monohydrate is added. After stirring the reaction solution at room temperature for 2 hours,
The reaction solution is poured into water and extracted with chloroform. After washing twice with saturated saline, the organic layer is dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (100:
When the solution eluted with the eluent of 1) is concentrated under reduced pressure, 5-
1.60 g of (4-chlorophenyl) -2-hydrazino-8-isopropyl-3H-pyrido [2,3-e] -1,4-diazepine are obtained as an orange oil. 5- (4-
Chlorophenyl) -2-hydrazino-8-isopropyl-3H-pyrido [2,3-e] -1,4-diazepine 2.0 g and toluene 25 ml were added to a uniform solution of 1.06 g of normal butyric anhydride and heated for 3 hours. Bring to reflux. After the reaction, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, then saturated aqueous sodium hydrogen carbonate solution, and saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure to give an orange residue. The residue is subjected to silica gel column chromatography, and the solution eluted with a chloroform-methanol (100: 1) eluent is concentrated under reduced pressure to obtain pale yellow crystals. The crystals were recrystallized from ethanol to give 6- (4-chlorophenyl) -9.
-Isopropyl-1-propyl-4H-pyrido [3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] White powdery crystals of diazepine are obtained. Melting point 204-
205 ° C. Reference Example 2 6-having a melting point of 214 to 215 ° C.
(4-Chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine was obtained.

Example 1 6- (4-chlorophenyl) -in 30 ml of diethyl carbonate
9-isopropyl-1-methyl-4H-pyrido [3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] Add 1.0 g of diazepine and 0.20 g of 60% sodium hydride and heat. After refluxing for 5 hours, 20 ℃
Then, 2.1 g of O- (2,4-dinitrophenyl) hydroxylamine is added and the mixture is stirred for 2 hours. After the reaction, the reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous magnesium sulfate. After filtering off anhydrous magnesium sulfate, the solution is concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, chloroform-methanol (100: 1).
The solution eluted with was concentrated to give ethyl (4-amino-6- (4-chlorophenyl) -9-, mp 214-215 ° C.
Isopropyl-1-methyl-4H-pyrido [3,2-
f] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-4-yl) carboxylate 0.82
get g. Ethyl (4-amino-6- (4-chlorophenyl)) was added to a mixture of 70 ml of ethanol and 13 ml of water.
-9-Isopropyl-1-methyl-4H-pyrido [3,3
2-f] [1,2,4] triazolo [4,3-a]
[1,4] diazepin-4-yl) carboxylate 0.71 g was dissolved and barium hydroxide octahydrate 0.55
g, and stirred at room temperature for 24 hours. After the reaction, the mixture is acidified to pH 2 with 1N hydrochloric acid, neutralized with an aqueous sodium hydrogen carbonate solution, and extracted with chloroform.
The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography. A solution eluted with a mixed solvent of chloroform-methanol (10: 1) was concentrated under reduced pressure to give an orange oily substance 4
-Amino-6- (4-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f] [1,
0.25 g of 2,4] triazolo [4,3-a] [1,4] diazepine are obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (6H, d, J = 7.9Hz), 2.76 (3H, s),
3.18 (1H, m, J = 7.9Hz), 1.54-1.88 (2H, bs), 5.01 (1H, s),
7.10-7.76 (6H, m)

Example 2 In the same manner as in Example 1, 6- (4-chlorophenyl)-
9-isopropyl-1-propyl-4H-pyrido [3,3
2-f] [1,2,4] triazolo [4,3-a]
[1,4] Diazepine to 4-amino-6- (4-chlorophenyl) -9-isopropyl-1-propyl-4H
-Pyrido [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine is obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 8Hz), 1.36 (6H, d, J = 6.4
Hz), 1.72 (2H, m, J = 8Hz), 1.84-2.28 (2H, bs), 2.98-3.32
(3H, m), 5.00 (1H, s), 7.08-7.72 (6H, m) Example 3 4-amino-6- (4-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido in 8 ml of chloroform. [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepine 0.20 g is dissolved, 3-methylphenylisocyanate 0.08 ml is added, and the mixture is stirred for 2 hours. The reaction solution was subjected to silica gel column chromatography, and the solution eluted with a solution of chloroform-methanol (50: 1) was concentrated under reduced pressure to give white crystals 0.2
2 g are obtained. When this was recrystallized from a mixed solvent of hexane and ethyl acetate, N- (6-
(4-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl)
0.10 g of -N '-(3-methylphenyl) urea is obtained. Example 4 4-amino-6- (4-chlorophenyl) -9-isopropyl-1-propyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4 , 3
-A] melting point 237-238 ° C from [1,4] diazepine
N- (6- (4-chlorophenyl) -9-isopropyl-1-propyl-4H-pyrido [3,2-f] [1,
2,4] triazolo [4,3-a] [1,4] diazepin-4-yl) -N ′-(3-methylphenyl) urea is obtained.

The following compounds are produced in the same manner as in the above example. (5) N- (6- (2-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f]
[1,2,4] Triazolo [4,3-a] [1,4] diazepin-4-yl) -N '-(2-methoxyphenyl) urea (6) N- (6- (2-chlorophenyl) -1, 9-
Dimethyl-4H-pyrido [3,2-f] [1,2,4]
Triazolo [4,3-a] [1,4] diazepine-4-
Yl) -N ′-(4-methoxyphenyl) urea (7) N- (1-methyl-5-phenyl-2-oxo-1,3-dihydro-2H-pyrido [2,3-e]
[1,4] diazepin-3-yl) -N '-(3-methylphenyl) urea (8) N- (5- (2-chlorophenyl) -1-methyl-8-isopropyl-2-oxo-1 , 3Dihydro-2H-pyrido [2,3-e] [1,4] diazepine-
3-yl) -2-indolecarboxamide (9) N-phenyl- (6- (4-chlorophenyl)
-1-Methyl-4H-pyrido [3,2-f] [1,2,
4] Triazolo [4,3-a] [1,4] diazepine-
4-yl) acetamide (10) N- (3-methylphenyl)-(6- (4-chlorophenyl) -1,9-dimethyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4,3-
a] [1,4] diazepin-4-yl) acetamide (11) N- (3-chlorophenyl)-(6- (4-chlorophenyl) -9-isopropyl-1-methyl-4H
-Pyrido [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl) acetamide (12) N- (2-methoxyphenyl)-(6 -(4-
Chlorophenyl) -1-methyl-9-phenyl-4H-
Pyrido [3,2-f] [1,2,4] triazolo [4,4
3-a] [1,4] diazepin-4-yl) acetamide (13) N- (3-methoxyphenyl)-(6- (4-
Chlorophenyl) -1-methyl-4H-pyrido [3,2
-F] [1,2,4] triazolo [4,3-a] [1,
4] diazepin-4-yl) acetamide (14) N- (6- (4-chlorophenyl) -1,9-
Dimethyl-4H-pyrido [3,2-f] [1,2,4]
Triazolo [4,3-a] [1,4] diazepine-4-
Yl) -p-toluenesulfonamide (15) N- (6- (2-chlorophenyl) -9-isopropyl-1-methyl-4H-pyrido [3,2-f]
[1,2,4] Triazolo [4,3-a] [1,4] diazepin-4-yl) -p-toluenesulfonamide (16) (5- (4-chlorophenyl) -8-isopropyl-1- Methyl-2-oxo-1,3-dihydro-2
H-pyrido [2,3-e] [1,4] diazepine-3-
Yl) -N- (3-methylphenyl) carbamate (17) (6- (2-chlorophenyl) -1,9-dimethyl-4H-pyrido [3,2-f] [1,2,4] triazolo [4] , 3-a] [1,4] diazepin-4-yl) -N- (3-methylphenyl) carbamate

Similarly, the compounds shown in the following table are prepared. Note: Me is methyl, Et is ethyl, CHMe ₂ is isopropyl, and Ph is phenyl.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location A61K 31/55 AED 9360-4C (72) Inventor Hiroshi Yasumatsu Yoshitomi-cho, Chikage-gun, Fukuoka 955 Small holiday Address: Central Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd. (72) Hirotsugu Komatsu, 3-7-25 Oyada, Iruma City, Saitama Prefecture, Tokyo Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): [In the formula, Ar represents an aryl which may have a substituent or a heteroaryl which may have a substituent. Ring A represents the following pyridine ring. [Chemical 2] R ¹ and R ² are the same or different and each have hydrogen, halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, aryl which may have a substituent or a substituent. Optionally represents heteroaryl. Or R
¹ and R ² may be bonded to each other to have a substituent 6
A member ring can be formed. R ³ has the formula: — (CH ₂ ) aN (R ⁴ ) CZN (R ⁵ ) (R ⁶ ) (1) (In the formula, a represents 0 or an integer of 1 to ^6. Z is an oxygen atom or a sulfur atom. R ⁴ is hydrogen and has 1 to 20 carbon atoms.
Represents an aralkyl which may have one alkyl or a substituent. R ⁵ and R ⁶ are the same or different and each represents hydrogen, an alkyl having 1 to 20 carbon atoms, a cycloalkyl which may have a substituent, a cycloalkylalkyl which may have a substituent, and a substituent. The aryl which may have, the aralkyl which may have a substituent, the heteroaryl which may have a substituent, or the heteroarylalkyl which may have a substituent are shown. Group represented by the formula:-(CH ₂ ) aN (R ⁴ ) COR ⁷ (2) (In the formula, a represents 0 or an integer of 1 to 6. R ⁴ is hydrogen and has 1 to 20 carbon atoms. R ⁷ represents an alkyl or aralkyl which may have a substituent, R ⁷ is alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, and 2 carbons.
To 20 alkynyl, aryl optionally having substituent (s), heteroaryl optionally having substituent (s), aralkyl optionally having substituent (s) or hetero optionally having substituent (s) Indicates an arylalkyl. ) By a group represented or _{formula,: - (CH 2) aN} (R 4) SO 2 R 9 (3) - (CH 2) aN (R 4) COOR 10 (4) - (CH 2) aOCON (R ^{11) (R 12) (5} ) - (CH 2) aCON (R 13) (R 14) (6) - (CH 2) aOCOR 15 (7) - (CH 2) aOSO 2 R 16 (8) - ( CH ₂ ) aCOR ¹⁷ (9), and — (CH ₂ ) aS (O) nR ¹⁸ (10) (In the formula, a represents 0 or an integer of 1 to 6. R ⁴ is hydrogen and has 1 to 20 carbon atoms. Aralkyl which may have one alkyl or a substituent, R ⁹ and R ^{10 each} have 1 to ¹⁰ carbon atoms.
20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, substituent An aryl, which may have
The heteroaryl which may have a substituent, the aralkyl which may have a substituent, or the heteroarylalkyl which may have a substituent are shown. R ¹¹ , R ¹² or R ¹³ , R ¹⁴ are the same or different and each have hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, and a substituent. And aryl which may be substituted, heteroaryl which may have a substituent, aralkyl which may have a substituent or heteroarylalkyl which may have a substituent. R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are each 1 to 20 carbon atoms.
Alkyl, aryl optionally having substituent (s), heteroaryl optionally having substituent (s), aralkyl optionally having substituent (s) or heteroarylalkyl optionally having substituent (s) Indicates. n is 0, 1 or 2
Indicates. ) Represents a group selected from. X represents an oxygen atom or a sulfur atom. Y is hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, aralkyl which may have a substituent,
A heteroarylalkyl which may have a substituent, or a formula: — (CH ₂ ) bCOOR ¹⁹ (wherein R ¹⁹ is hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons or Represents an aralkyl which may have a substituent, and b represents an integer of 1 to 6). Or, X and Y are bonded to each other and = NN-C
(R ²⁰⁾ - or = N-CH = C (R 20) - ( wherein,
R ²⁰ is hydrogen, halogen, alkyl having 1 to 20 carbons,
Alkenyl having 2 to 20 carbon atoms, alkynyl having 2 to 20 carbon atoms, cycloalkyl which may have a substituent,
A cycloalkylalkyl which may have a substituent, an aryl which may have a substituent, a heteroaryl which may have a substituent, an aralkyl which may have a substituent, and a substituent A heteroarylalkyl which may have or a formula: — (CH ₂ ) bCOOR ²¹ (wherein R is
²¹ is hydrogen, alkyl having 1 to 20 carbons, 2 to 2 carbons
It represents aralkyl which may have 0 alkenyl or a substituent. b shows the integer of 1-6. ) Shows the group represented by. ) Shows the group represented by. ] The pyridodiazepine compound represented by these, or its pharmaceutically acceptable salt. 2. A general formula: (In the formula, each symbol is as defined in claim 1.) A pyridodiazepine compound represented by the formula or a pharmaceutically acceptable salt thereof. 3. A general formula: (In the formula, each symbol is as defined in claim 1.) A pyridodiazepine compound represented by the formula or a pharmaceutically acceptable salt thereof. 4. A general formula: (In the formula, each symbol is as defined in claim 1.) A pyridodiazepine compound represented by the formula or a pharmaceutically acceptable salt thereof. 5. A general formula: (In the formula, each symbol is as defined in claim 1.) A pyridodiazepine compound represented by the formula or a pharmaceutically acceptable salt thereof.